EURURO Vol. 72 No. 2

E32 320

Letter to the Editor
Re: Cesare Cozzarini. Whole-pelvis Radiotherapy in the
Radiation Treatment of Intermediate- and High-risk
Prostate Cancer: How to Improve the Therapeutic
Ratio of a Potentially Effective but still Unsatisfactory
Treatment? Eur Urol 2017;71:44–5
Preclinical Combinatorial Approach to Enhance
Radiotherapy Effects and Reduce its Morbidity May Be
Tested in the Clinic
Reading the Platinum Priority Editorial by Cozzarini on
the possibility that ‘‘whole-pelvis radiotherapy (RT) in the
setting of radical radiation treatment of clinically localized
prostate carcinoma’’ may improve clinical outcomes at the
plausible cost of higher morbidity (hematologic issues are
mainly highlighted by Cozzarini), I would like to highlight
the results of several recent preclinical studies searching for
a better effect of RT by (1) increasing the effects of RT with
new radiosensitizers that will allow a reduction in RT dose
while preserving its benefits and (b) improving the post-RT
effect by extending the anticancer activity. Although these
observations are ‘‘off target’’ concerning the goals of the
editorial, they may be valuable in planning future research
to test their feasibility and true benefits.
A clinical formulation of hybrid manganese dioxide
nanoparticles (MDNPs) using biocompatible materials to
re-oxygenate the tumor microenvironment (TME) via
reaction with endogenous H2O2 has been proposed as an
adjuvant in treating tumors with RT . In a murine model,
approximately 40% of tumor-bearing mice were tumor-free
after a single treatment with MDNPs + RT at a 2.5-fold lower
dose than required to achieve the same curative treatment
without MDNPs. Nevertheless, the authors stated ‘‘Ideally
100% curative treatment is desirable . . . including the
combination therapy of MDNPs and RT studied here.
However, there always are poor-responding individuals
in clinic and preclinical studies due to a variety of factors . . .
we believe that heterogeneity in tumors . . . plays a role in
the nonuniform response to the treatment’’.
Hypoxia in the TME causes resistance to RT and
contributes to poor prognosis in patients by increasing
HIF-1 . Moreover, inhibition of HIF-1 during the post-RT
period can increase tumor radiosensitivity . RT induces
secretion of VEGF and triggers endothelial radioresistance
These findings suggest that tumors actively protect
themselves from secondary radiation damage by promoting
aberrant vasculogenesis. Treatment with MDNPs + RT
restricts this effect by increasing oxygen before each RT
intervention; once this treatment is over, the increased
angiogenesis remains via the HIF-1 that persists in the
tumoral and endothelial cells that survive .
Several preclinical studies have shown a benefit of
combining RT with drugs that inhibit tumor blood vessel
growth Recent findings show that proper scheduling of
both treatment modalities allows dose reductions for both
RT and angiostatic drugs without affecting their therapeutic
efficacy . The increased expression of angiogenic factors
such as VEGF after RT appears to be functionally relevant,
and inhibition of VEGF receptor signaling with sunitinib
counteracted the increased perfusion, and thus augmented
the antitumoral effect of RT . Moreover, tumor growth
inhibition was observed with low-dose sunitinib, avoiding
the serious adverse effects of this angiostatic agent at
conventional doses. Therefore, this combinatorial approach
(RT + MDNPs + a low dose of an antiangiogenic drug/
antibody) might be testable in the clinic to verify if it actually
reduces the adverse effects of RT with heightened therapeu-
tic results and lower recurrence risk.
Conflicts of interest: The author has nothing to disclose.
References
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available at
journal homepage:
DOI of original article: .
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.